Transcription factors represent a group of molecules within the cell that function to connect the pathways from extracellular signals to intracellular responses.
Immediately after an environmental stimulus, these proteins which reside predominantly in the cytosol are translocated to the nucleus where they bind to specific DNA sequences in the promoter elements of target genes and activate the transcription of these target genes.
Glioma-associated oncogene-1 (also known as GLI and GLI-1) is a nuclear protein containing 5 zinc fingers connected by a highly conserved sequence of 7 amino acids termed the H/C link, a region which has homology to the Kruppel family of zinc finger transcription factors (Kinzler et al., Nature, 1988, 332, 371-374). The isolation of other GLI-related proteins has lead to the classification of these proteins into a separate sub-family of transcription factors, the Kruppel-related gene family or the GLI-Kruppel family. Seven members of the family have been isolated in humans; four of which are GLI proteins (Ruppert et al., Mol. Cell. Biol., 1988, 8, 3104-3113).
Glioma-associated oncogene-1 was originally cloned from a glioma cell line where it was shown to be amplified more than 50-fold (Kinzler et al., Science, 1987, 236, 70-73; Kinzler et al., Nature, 1988, 332, 371-374). In fact, expression of the protein in the central nervous system is a rare event and the elevated levels observed are associated with amplification of the gene (Xiao et al., Pediatr. Neurosurg., 1994, 20, 178-182). Subsequently it been shown to have oncogenic potential in other cell types (Ruppert et al., Mol. Cell. Biol., 1991, 11, 1724-1728). Additionally, the glioma-associated oncogene-1 gene is located in a chromosomal region that is affected by translocations in a variety of benign and malignant tumors (Kinzler et al., Science, 1987, 236, 70-73).
Overexpression of glioma-associated oncogene-1 has been demonstrated in all sporadic human basal cell carcinomas examined (Dahmane et al., Nature, 1997, 389, 876-881) as well as in medulloblastoma and rhabdomyosarcomas in mutant mice (Hahn et al., J. Mol. Med., 1999, 77, 459-468). It is also amplified in several childhood sarcomas including osteosarcoma, rhabdomyosarcoma and liposarcoma (Roberts et al., Cancer Res., 1989, 49, 5407-5413).
The pharmacological modulation of glioma-associated oncogene-1 activity and/or expression may therefore be an appropriate point of therapeutic intervention in pathological conditions such as cancers of the central nervous system, skin and musculoskeletal system.
To date, strategies aimed at investigating glioma-associated oncogene-1 function have involved the use of antibodies and immunohistochemical methods to identify expression patterns and cellular localization (Ghali et al., J. Invest. Dermatol., 1999, 113, 595-599). Truncated mutants of the GLI proteins have also been used to define the context-dependent positive and negative roles of the individual members of the family (Altaba, Development, 1999, 126, 3205-3216).
Currently, there are no known therapeutic agents that effectively inhibit the synthesis of glioma-associated oncogene-1. Consequently, there remains a long felt need for these agents.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of glioma-associated oncogene-1 expression.
The present invention provides compositions and methods for modulating glioma-associated oncogene-1 expression.